Key result
Doxorubicin induces cardiac cell apoptosis through the activation of the ERK1/2-p53 signal transduction pathway, which can be significantly attenuated by specific ERK1/2 and p53 inhibitors.
The ERK1/2-p53 signaling cascade mediates doxorubicin-induced apoptosis in cardiomyocytes, identifying these molecules as potential therapeutic targets to prevent doxorubicin-induced cardiotoxicity.
Identifies ERK1/2-p53 inhibition as a potential cardioprotective target against doxorubicin; hypothesis-generating in animal models and leaves open human translation.
The cardiotoxic effects of doxorubicin, a potent chemotherapeutic agent, have been linked to DNA damage, oxidative mitochondrial damage, and nuclear translocation of p53, but the exact molecular mechanisms causing p53 transactivation and doxorubicin-induced cardiomyopathy are not clear. The present study was carried out to determine whether extracellular signal-regulated kinases (ERKs), which are known to be activated by DNA damaging agents, are responsible for doxorubicin-induced p53 activation and oxidative mitochondrial damage in H9c2 cells. Cell death was measured by terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling, annexin V-fluorescein isothiocyanate, activation of caspase-9 and -3, and cleavage of poly(ADP-ribose) polymerase (PARP). We found that doxorubicin produced cell death in H9c2 cells in a time-dependent manner, beginning at 6 h, and these changes are associated decreased expression of Bcl-2, increases in Bax and p53 upregulated modulator of apoptosis-alpha expression, and collapse of mitochondria membrane potential. The changes in cell death and Bcl-2 family proteins, however, were preceded by earlier activation and nuclear translocation of ERKs, followed by increased phosphorylation at Ser15 and nuclear translocation of the phosphorylated p53. The functional importance of ERK1/2 and p53 in doxorubicin-induced toxicity was further demonstrated by the specific ERK inhibitor U-0126 and p53 inhibitor pifithrin (PFT)-alpha, which abrogated the changes in Bcl-2 family proteins and cell death produced by doxorubicin. U-0126 blocked the phosphorylation and nuclear translocation of both ERK1/2 and p53, whereas PFT-alpha blocked only the changes in p53. Doxorubicin and ERK inhibitors produced similar changes in ERK1/2-p53, PARP, and caspase-3 in neonatal rat cultured cardiomyocytes. Thus we conclude that ERK1/2 are functionally linked to p53 and that the ERK1/2-p53 cascade is the upstream signaling pathway responsible for doxorubicin-induced cardiac cell apoptosis. ERKs and p53 may be considered as novel therapeutic targets for the treatment of doxorubicin-induced cardiotoxicity.
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Liu et al. (2008) studied Doxorubicin-induced cardiotoxicity. Doxorubicin vs. Untreated control cells was evaluated on Cell apoptosis and ERK1/2-p53 pathway activation. Doxorubicin induces cardiac cell apoptosis through the activation of the ERK1/2-p53 signal transduction pathway, which can be significantly attenuated by specific ERK1/2 and p53 inhibitors.
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